Our studies of T cell activation led us to consider the role of physiologically abundant, "nonimmune", small signaling molecules of extracellular ATP and adenosine and their receptors in lymphocyte development and effector functions. We found that extracellular adenosine suppresses all tested TCR-triggered effector functions of T lymphocytes, including TCR-triggered FasL mRNA upregulation in cytotoxic T lymphocytes (CTL), granule exocytosis, perforin-mediated cytotoxicity, and T cell proliferation. The "memory" of T cells to exposure to adenosine was best explained by sustained increases in [cAMP]. Biochemical and genetic studies using A2a adenosine receptor deficient mice demonstrate that A2a receptors are solely responsible for adenosine-triggered cAMP increases and direct apoptotic effects of extracellular adenosine on T cells. It is established that effects of extracellular adenosine on T cells and thymocytes are mediated by adenosine receptor-mediated signaling rather than by intracellular toxicity of adenosine catabolites. The use of A2a receptor deficient mice also revealed the existence of A2a receptor independent pathway of effects of extracellular Adenosine on T cell activation.